Dataset Information

Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation.

ABSTRACT:

Background

Airway tolerance is critical for protecting the lung from inflammatory disease driven by allergens. However, factors that disrupt tolerance processes and then lead to susceptibility to developing allergic asthma remain elusive.

Objective

To investigate whether recognition of bacterial microbial-associated molecular patterns in the lung may result in susceptibility to developing allergic reactions, and to understand the molecular mechanisms by which such triggers block natural tolerance.

Methods

Ligands of intracellular microbial-associated molecular pattern recognition receptors-the nucleotide-binding oligomerization domain (Nod)-like receptors, Nod1 and Nod2-were given intranasally with antigen, and their ability to modulate airway tolerance was analyzed.

Results

Intranasal Nod2 ligand rapidly induced lung expression of the innate cytokines thymic stromal lymphopoietin and IL-25, and thymic stromal lymphopoietin promoted expression of OX40 ligand, a T-cell-costimulatory ligand, on lung CD11c(+)CD11b(+) cells and B220(+) cells. Together these 3 molecules blocked the generation of antigen-specific CD4(+)forkhead box protein 3(+) adaptive regulatory T cells and concomitantly drove IL-4-producing CD4 T cells. By altering the regulatory T/T(H)2-cell balance, tolerance was blocked, and sensing of Nod2 ligand resulted in subsequent susceptibility to developing eosinophil-dominated airway inflammation.

Conclusion

We show that a Nod-like receptor is a novel, previously unrecognized, pathway that adversely links innate and adaptive immunity and leads to allergic disease and asthmatic lung inflammation.

SUBMITTER: Duan W

PROVIDER: S-EPMC3058679 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation.

Duan Wei W Mehta Amit K AK Magalhaes Joao G JG Ziegler Steven F SF Dong Chen C Philpott Dana J DJ Croft Michael M

The Journal of allergy and clinical immunology 20101104 6

<h4>Background</h4>Airway tolerance is critical for protecting the lung from inflammatory disease driven by allergens. However, factors that disrupt tolerance processes and then lead to susceptibility to developing allergic asthma remain elusive.<h4>Objective</h4>To investigate whether recognition of bacterial microbial-associated molecular patterns in the lung may result in susceptibility to developing allergic reactions, and to understand the molecular mechanisms by which such triggers block n ...[more]

PMID: 21051079

Similar Datasets

Project description:Group 2 innate lymphoid cells (ILC2) are implicated in allergic asthma as an early innate source of the type 2 cytokines IL-5 and IL-13. However, their induction in house dust mite (HDM)-mediated airway inflammation additionally requires T cell activation. It is currently unknown whether phenotypic differences exist between ILC2s that are activated in a T cell-dependent or T cell-independent fashion. Here, we compared ILC2s in IL-33- and HDM-driven airway inflammation. Using flow cytometry, we found that surface expression levels of various markers frequently used to identify ILC2s were dependent on their mode of activation, highly variable over time, and differed between tissue compartments, including bronchoalveolar lavage (BAL) fluid, lung, draining lymph nodes, and spleen. Whereas in vivo IL-33-activated BAL fluid ILC2s exhibited an almost uniform CD25+CD127+T1/ST2+ICOS+KLRG1+ phenotype, at a comparable time point after HDM exposure BAL fluid ILC2s had a very heterogeneous surface marker phenotype. A major fraction of HDM-activated ILC2s were CD25lowCD127+T1/ST2low ICOSlowKLRG1low, but nevertheless had the capacity to produce large amounts of type 2 cytokines. HDM-activated CD25low ILC2s in BAL fluid and lung rapidly reverted to CD25high ILC2s upon in vivo stimulation with IL-33. Genome-wide transcriptional profiling of BAL ILC2s revealed ~1,600 differentially expressed genes: HDM-stimulated ILC2s specifically expressed genes involved in the regulation of adaptive immunity through B and T cell interactions, whereas IL-33-stimulated ILC2s expressed high levels of proliferation-related and cytokine genes. In both airway inflammation models ILC2s were present in the lung submucosa close to epithelial cells, as identified by confocal microscopy. In chronic HDM-driven airway inflammation ILC2s were also found inside organized cellular infiltrates near T cells. Collectively, our findings show that ILC2s are phenotypically more heterogeneous than previously thought, whereby their surface marker and gene expression profile are highly dynamic.

Dataset Information

Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation.

Background

Objective

Methods

Results

Conclusion

Publications

Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets